The invention relates to new macrocyclic polymer complexing agents and complexes, agents containing these compounds, the use of the complexes in diagnosis and treatment as well as processes for the production of these compounds and agents.
Magnevist.RTM. (GdDTPA/dimeglumine) is the first recorded contrast medium for nuclear spin tomography (MRI=Magnetic Resonance Imaging). It is especially well-suited for the diagnosis of pathological areas (e.g., inflammations, tumors, etc.). The compound is eliminated through the kidneys after intravenous injection; an extrarenal elimination is practically not observed.
A drawback of Magnevist.RTM. is that after intravenous administration it is uniformly distributed between the vascular and the interstitial space. Thus, defining the limits of the vessels relative to the surrounding interstitial space when using Magnevist.RTM. is not possible.
A contrast medium which is distributed exclusively in the vascular space (vessel space) would be desirable especially for the representation of vessels. Such a blood-pool agent is to make it possible to differentiate, with the help of nuclear spin tomography, tissue that is well supplied by blood from tissue poorly supplied with blood and thus to diagnose an ischemia. It would also be possible to differentiate infarcted tissue because of its anemia from the surrounding healthy or ischemic tissue, when a vascular contrast medium is used. This is of special importance if it is, e.g., a matter of differentiating a myocardial infarction from an ischemia.
Therefore, there is a need for contrast media which can label the vascular space (blood-pool agent). These compounds are to be distinguished by a good compatibility and by a high effectiveness (high increase of the signal intensity with MRI).
Macromolecules are generally suitable as contrast media for angiography. But albumin-GdDTPA (Radiology 1987, 162: 205), e.g., in the rat shows a concentration in hepatic tissue, which constitutes almost 30% of the dose, 24 hours after intravenous injection. Further, only 20% of the dose is eliminated within 24 hours.
The macromolecule polylysine-GdDTPA (European patent application, publication no. 0 233 619) proved suitable as blood-pool agent. But it shows the drawback that the openchain complexing agent DTPA in the desired prolonged retention times of the contrast medium in the body does not optionally bind the metal ions. This applies also to the carbohydrate complexes claimed in European patent application 0 186 947, as well as to the macromolecules labeled with radioisotopes described in J. Med. Chem. 1974, Vol. 17, 1304.
Recently, amides of macrocyclic complexing agents for bonding to macromolecules were proposed in PCT WO 90/12050. But, as is generally known, by conversion of one of the carboxy groups of 1,4,7,10-tetraazacyclododecane-tetraacetic acid (DOTA) to an amide group, the stability constant of the gadolinium complex is reduced by four orders of magnitude (A. D. Sherry et al., Inorg. Chem. 1989, 28, 620), so that the problem of cleavage of toxic metal ions from the macromolecular complexes was still not able to be satisfactorily solved in this way.